Abstract
Intermittent fasting (IF), an emerging dietary strategy alternating fasting and feeding cycles, exerts multi-modal brain protection through the regulation of the gut-brain axis. With neurological and mental disorders ranking among the top global disease burdens, IF opens new frontiers in nutritional neuroscience by modulating gut microbiota composition and metabolic pathways, offering a non-pharmacological intervention strategy. Preclinical studies reveal that IF enriches probiotics, reduces neuroinflammation, and restores intestinal barrier integrity, thereby mitigating "leaky gut"-induced cognitive decline. Similarly, the ketogenic effect of IF can improve mitochondrial efficiency, while its anti-inflammatory effect alleviates the pathological changes of multiple sclerosis by suppressing autoreactive T cells. Clinical evidence reveals that IF significantly correlates with decreased β-amyloid burden in Alzheimer's disease (AD) transgenic models and enhanced motor performance in Parkinson's disease (PD) patients, suggesting its multimodal neuroprotective effects. Mental health benefits are equally striking: IF rebalances the Firmicutes-to-Bacteroidetes ratio, which has been linked to anxiety and depression remission. The gut-brain axis (GBA) emerged as a pivotal mediator, with short-chain fatty acids (SCFAs) and tryptophan derivatives fostering serotonin synthesis and oxidative stress reduction. This review synthesizes preclinical and clinical evidence demonstrating how intermittent fasting modulates the gut-microbiota-metabolite-brain axis to promote neuroprotection and mental health benefits, while identifying personalized protocol optimization as a critical avenue for future research.